D-serine suppresses cytotoxic T-cell activity in gastric tumors and may aid resistance against immune checkpoint inhibitors

Researchers from Keio University have found that D-serine increases the growth of gastric cancer by creating an immunosuppressive and anti-inflammatory tumor microenvironment. Higher levels of D-serine in serum correlated with greater immune checkpoint inhibitor therapy resistance in tumors. Suppressing D-serine in circulation could improve the efficacy of immunotherapies against gastric cancer. These findings position D-serine within the broader field of cancer amino acid metabolism and point to it as a possible target for tumor evasion.

One of the crucial steps in cancer proliferation is evading killer immune cells. Cancer cells use a variety of signaling molecules to evade the immune system. Immune checkpoint inhibitor (ICI) therapy interferes with some of these evasion tactics, improving the immune system’s ability to suppress tumors. However, the success of ICI therapy depends on the specific signals being secreted by the tumor.

Recent research has identified D-amino acids (D-AAs) as a new class of signaling molecules. D-AAs are enantiomers, or “mirror images” of L-amino acids that make up proteins. D-AAs are normally present in human biological fluids and can be derived from the diet, microbiota, and metabolic byproducts. "Our previous research showed that oral administration of D-AAs improved colitis in a mouse model,” says Assistant Professor Shohei Suzuki, from the Keio University School of Medicine.

Could D-AAs play a role in tumor immunity? That is the question Dr. Suzuki sought to answer. With support from Assistant Professor Kai Tsugaru and Associate Professor Tomohisa Sujino, also from the School of Medicine, the research team studied the effects of D-AAs, specifically D-serine (D-ser), in mouse models of GC and in human patients. Their findings were made available online in the journal eBioMedicine on July 31, 2026.

The team induced gastric cancer (GC) in healthy mice and injected the tumors with various solutions of D-AAs and L-AAs. Only mice that received D-ser showed significantly faster tumor growth compared to controls. Further analysis showed that D-ser had major immunosuppressive effects. D-ser administration increased both the numbers and activity of anti-inflammatory immune cells in the tumor microenvironment, particularly M2-like macrophages. As a result, CD8⁺ cytotoxic T cells, which would otherwise kill GC tumor cells, were in much smaller numbers and their activity was greatly reduced.

Further studies showed that tumor-associated macrophages (TAMs) in D-ser-injected tumors secreted excessive amounts of two immunosuppressive molecules, fibronectin 1 (FN1) and secreted phosphoprotein 1 (SPP1), both known to suppress CD8⁺ T cells. When anti-SPP1 antibodies were injected into the D-ser-enhanced tumors, tumor growth rate decreased, approaching that of the low-D-ser phenotype.

The researchers then examined clinical records across multiple human cohorts. "We discovered that the concentration of D-ser in the serum of patients with GC was higher than that of healthy control," says Dr. Suzuki. What’s more, the concentration of D-ser in serum was correlated with resistance to ICI therapy; patients with stage IV, ICI-resistant GC tumors had the highest D-ser concentrations in their bloodstream.

"Although ICIs have become a first-line treatment option for GC, better predictors of treatment response are needed due to the risk of immune-related adverse events,” says Dr. Suzuki. These findings show that serum D-ser could serve as a biomarker for both GC itself and the likelihood of ICI resistance in patients with the disease.

Encouraged by these results, Dr. Suzuki identified directions for future research in this field. "We are now investigating whether D-ser levels in blood and feces can help predict how patients respond to ICI therapy. Ultimately, we hope to develop new treatments that target D-ser and the gut bacteria that produce it," says Dr. Suzuki. Dr. Sujino adds, "A strategy to reduce the concentration of D-ser in the serum of patients with tumors might regulate immune activity against cancer,” indicating that D-ser and its downstream signaling molecules may be potential new targets for anti-GC immunotherapies.

Reference
Title of original paper: D-serine as a metabolic immune checkpoint in the tumour microenvironment
Journal: eBioMedicine
DOI: https://doi.org/10.1016/j.ebiom.2026.106402

About Keio University Global Research Institute (KGRI), Japan
The Keio University Global Research Institute (KGRI), established in November 2016, serves as a university-wide platform connecting faculties and graduate schools. It promotes interdisciplinary and international collaborative research that transcends academic and geographic boundaries, while disseminating research outcomes both domestically and globally.
In 2024, Keio University launched the Program for Forming Japan’s Peak Research Universities (J-PEAKS), funded by the Japan Society for the Promotion of Science (JSPS), under the vision of becoming a “research university that forges the common sense of the future.” Through this initiative, KGRI is strengthening research infrastructure to enhance interdisciplinary collaboration, promoting the societal implementation of research, and fostering a research ecosystem that enables collaboration across the university and with leading institutions in Japan and abroad.
Website: https://www.keio.ac.jp/en/org/kgri/

About Associate Professor Tomohisa Sujino from Keio University School of Medicine
Tomohisa Sujino is an Associate Professor at the Keio University School of Medicine, where he heads the Department of Multidimensional Analysis of Gastrointestinal Biology at The Sakaguchi Laboratory. His research focuses on mucosal immunology, particularly how the microbiome and intestinal antigens influence the gut microenvironment and contribute to disease. Read more about his research here: https://www.keio-sujino-lab.com/ https://k-ris.keio.ac.jp/html/100002951_en.html https://researchmap.jp/tsujino

About Assistant Professor Shohei Suzuki from Keio University School of Medicine
Shohei Suzuki is an Assistant Professor at the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine. His research focuses on mucosal immunology and immune interactions between the gut and other organs. He received his M.D. from the University of Tsukuba in 2016 and completed clinical training in gastrointestinal endoscopy at Sendai City Medical Center. His work aims to elucidate how intestinal immune responses influence systemic diseases, including neuroinflammatory disorders. In addition to his research work, Dr. Suzuki is a practicing gastroenterologist.


Funding information

• The Japan Science and Technology Agency (JST) Fusion Oriented Research for Disruptive Science and Technology (FOREST) Grant JPMJFR210P
• Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) Grant Nos. .25K10430 21K18272, 23H02899, 23K27590, 25K22627,
• KGRI challenge grant
• Sakaguchi Memorial Foundation
• Japan Agency for Medical Research and Development (CREST) Grant 21gm1510002h0001

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